Use of pharmaceutical compositions in preparing pharmaceuticals for treating diabetic ulcer

ABSTRACT

The use of pharmaceutical compositions in preparing pharmaceuticals for treating diabetic ulcer in limb or on body surface, or in preparing medical dressing. The pharmaceutical compositions consist of (A) 3 to 15% by weight of edible beeswax and (B) 85 to 97% by weight of sesame oil extract of  Scutellaria  root,  Coptis  root,  Phellodendron  bark, earthworm and poppy capsule, based on the total weight of the pharmaceutical compositions. In the sesame oil extract, each of  Scutellaria  root,  Coptis  root,  Phellodendron  bark, earthworm and poppy capsule is in an amount of 2 to 10% by weight of dry raw material based on the total weight of sesame oil. A medical dressing for treating diabetic ulcer and corresponding medicine box enclosing the said dressing are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and is a continuation of, U.S.patent Ser. No. 13/132,066, filed on Aug. 3, 2011, now pending, which isthe national stage entry of International Application No.PCT/CN2010/070263, filed on Jan. 20, 2010, which claims priority fromChinese Patent Application No. 2009-10091355.5, filed on Aug. 20, 2009,all of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to use of pharmaceutical compositions inpreparing pharmaceuticals for treating diabetic ulcer in limb or on bodysurface, or in preparing medical dressing. This invention also relatesto a kind of medical dressing for treating diabetic ulcer in limb or onbody surface, and the corresponding medicine box enclosing the saiddressing.

BACKGROUND OF THE INVENTION

Chinese Patent ZL931002761 has disclosed a pharmaceutical compositionfor treating thermal injuries; the said pharmaceutical compositionconsists of (A) 3 to 15% of edible beeswax and (B) 85 to 97% of sesameoil extract of Huangqin, Huanglian, Huangbai, earthworm and poppycapsule, based on the total weight of the pharmaceutical composition. Inthe sesame oil extract, each of Huangqin, Huanglian, Huangbai, earthwormand poppy capsule is in an amount of 2 to 10% by weight of dry rawmaterial based on the total weight of sesame oil.

Furthermore, the pharmaceutical composition for treating thermalinjuries is mainly used in warm-blooded mammals or in human for treatingthermal injuries, including burns, especially burns of large areas,scalds, chemical ambustion, etc. It can also be used to treat sore andulcer of human, including wound surface ulcer, infected wound surface,vaginitis, cervical erosion, hemorrhoid, pressure ulcer, wound surface,congelation, and frostbite, etc.

TERMINOLOGY

-   -   1. ‘Pharmaceutical composition described in the present        invention’ or ‘Pharmaceutical composition of the present        invention’. It indicates a pharmaceutical composition consisting        of (A) 3 to 15% of edible beeswax and (B) 85 to 97% of sesame        oil extract of Huangqin (root of Scutellaria baicalensis        Georgi), Huanglian (root of Coptis chinensis Franch, C.        deltoidea C. Y. Cheng et Hsiao, or C. teeta Wall.), Huangbai        (bark of Phellodendron chinense Schneid or P. amurense Rupr),        earthworm and poppy capsule, based on the total weight of the        pharmaceutical composition. In the sesame oil extract, each of        Huangqin, Huanglian, Huangbai, earthworm and poppy capsule,        based on the total weight of the pharmaceutical composition. In        the sesame oil extract, each of Huangqin, Huanglian, Huangbai,        earthworm and poppy capsule is in an amount of 2 to 10% by        weight of dry raw material based on the total weight of sesame        oil.    -   2. Ulcer Persons skilled in the art agree that ulcer is one of        the common diseases, and treatment for ulcers is a routine        practice for clinical doctors. Although the definition of ulcer        seems self-evident, many professionals are not very familiar        with the difference between wound and ulcer. In general, a        tissue defect reaching down to dermis or subcutaneous tissue can        be called an ulcer, a suppurative ulcer of round shape with a        certain depth is called running sore, and small very deep        hole-like ulcer is called fistulous opening. Lever defined the        ulcer as a partial defect of dermis and epidermis of residual        scar after healing. On the other hand, Anderson's Pathology        thinks that inflammation developing in the vicinity of surface        of tissue or organ gives strong inflammatory stimuli and causes        tissue necrosis, and ulcers finally form after exfoliation of        necrotic tissue. So, in dermatology, from the viewpoint of        histology and morphology, an ulcer is a partial defect of dermis        and epidermis and does not necessarily require inflammation as a        prerequisite. But in pathology, inflammation first develops in        the superficial layer of the organ, and an ulcer forms following        shedding of necrotic tissue. Thus it can be seen that wound        falls into the category of ulcer in dermatology, but not in        pathology.

As to the relation of wound and ulcer, Siemens pointed out: Wound notcured for first time usually develops secondary infection, subsequently,granulation tissue will grow and cover the bottom of wound, in thissituation, the wound should be called an ulcer. It is worthy of notethat sometimes in China professionals call this kind of wound surface‘open wound’, and classify it into wound ulcer.

-   -   3. Skin ulcer Persons skilled in the art agree that skin ulcer        is a restricted skin defect that involves dermis or deeper        layers after skin injury, and scar will be left behind after        healing.    -   4. Diabetic ulcer The inventor of the present invention thinks        that diabetic ulcer is not a sore ulcer, wound surface ulcer or        ulcer with the above-mentioned meaning, but a special kind of        ulcer resulting from diabetes and happening to the lower        extremities and body surface tissue, with ulcer's        characteristics, and it mainly develops in the lower extremities        and is completely different in etiology or pathogenesis from        traumatic ulcer. So far, there are still no ideal and effective        pharmaceuticals for diabetic ulcer world wide.

The diabetic ulcer described in the present invention includes ulcers inlimb and ulcers on body surface of diabetic patient.

The pathogenetic mechanism of diabetic ulcer is very complicated, andthere is no unified and common clear understanding for the time being.In general, three interactive processes are involved: angiopathy,neuropathy, and immunopathy.

Angiopathy:

There are two large types of angiopathy, wherein one is the pathologicalchange in large blood vessels; the other is the pathological change inmicro-vessels. These pathological changes result in ischemia of softtissue in leg and on body surface, and finally evolve into ulcer.

Neuropathy:

Neuropathy participates in an early stage of pathogenesis of diabeticfoot ulcer, and is also the most important detrimental factor indiabetic foot ulcer. During this pathogenesis, all the neural functionsare damaged, but often, the longest and the thinnest nervous fiber,including the motor nerve that controls the foot muscles, is damagedfirst. Functional loss of lumbrical muscle leads to foot deformation,and this increases the pressure or friction in the sites ofsub-metatarsophalangeal joint, toe dorsum or toe tips and the like.These factors easily induce ulcers. Damage to autonomic nerve functionalso emerges in the earlier stage of neuropathy, causing a series ofpathological changes, including arteriovenous shunt, decreased tissueinfusion, alopecia, functional loss of sebaceous glands and sweatglands. These elements work together and result in skin dryness, scaleformation and liability to rhagades.

Immunopathy:

Role of immunopathy in diabetic infection is still in dispute, most ofthe researchers believe that the inefficient control of blood sugarcould make patients more vulnerable to infection. But as a matter offact, the humoral immunity in diabetic patients appears to be normal,blood immunoglobulin level is normal or a little higher, counting of Blymphocyte is normal, and in model mice, no antibody reaction orcomplement binding inefficiency was found.

For example, the main symptoms of diabetic foot are pain of leg,numbness, foot ulcer and acromelic gangrene resulted from angiopathy,neuropathy, and infection of leg. Clinically, it is often referred to asdiabetic foot (commonly called rotten foot), with the majormanifestations as follows:

-   -   1. Skin itching, dryness and anhidrosis, coldness of        extremities, edema and withering, darkening of skin color,        appearance of pigment plaques, lanugo exfoliation.    -   2. Stabbing pain, burning pain, numbness, dysesthesia or loss of        feeling of extremities, feeling like stamping on cotton, duck        gait, intermittent claudication, and rest pain.    -   3. Malnutrition of extremities, weakening of muscular tension,        joint ligaments liable to damage.    -   4. Depression of heads of metatarsal bones, metatarsophalangeal        joint curves and forms pes arcuatus, hammer toe, chicken claw        toe, Charcot's joint, destruction of bone can result in        pathological fracture, etc.    -   5. Pulsation of dorsal arteries of foot weakens or disappears;        deep and superficial reflexes retard or disappear.    -   6. Dry and fissured skin or skin blisters, bloody vesicle,        erosion, ulcer, gangrene or necrosis of extremities.

Under the present clinical techniques, diabetic patients oftensimultaneously suffer from many kinds of skin lesion, long-termmetabolic disorder, pathological changes of micro-vessels and peripheralnerves, these changes are also the decisive causes of skin ulcers.Long-term angiopathy makes blood vessel sclerotic and stenotic,especially in the lower extremities, and gives a negative effect onblood supply, further leading to skin malnutrition. Pathological changesin micro-vessels can lower the blood supply for endoneurium, andexacerbate the lesions of autonomic nerves. Pathological changes ofnerves can increase the threshold level of skin pain and pressure sense,and change pressure—bearing sites of planta, therefore, infection oftenoccurs to feet, especially toes. In this situation, if injuries happento the skin, the repair is often inefficient, and the skin will be verysusceptible to secondary infection, ulcer and gangrene for feet.Inducing factors in the first beginning of the disease are often obviousfor most of the patients, and wound is the most important one. Still,diabetic patients with athlete's foot, onychomycosis and long-term useof antibiotics are more vulnerable to foot fungal infection. For elderlydiabetic patients, due to long course of disease, less activities, lessefficient peripheral circulation, skin ulcer is more likely to occur. Onthe other hand, for elderly patients, hyperalycemia decreases the immunefunction, and the possibilities of infection after ulcerous formationwill be great, while cellulitis, osteomyelitis, septicemia, etc. mayoccur in the serious cases, in which amputation rate will increasesignificantly. Generally, diabetic ulcers should be treated withsystematic medical therapy, including blood sugar control,anti-infection, improvement of microcirculation and topical managementof wound areas, for example, using cephalosporins, lincomycin,penicillin, clarithromycin, aciclovir, amoxicillin and dicloxacillinsodium capsules, compound sulfamethoxazole and the like as measures foranti-infection; using mupirocin ointment externally, etc. But once thatdiabetic ulcer occur, there will be no ideal and effective therapy forcuring this ulcerous wound surface, surgical amputation is still oftenadopted for the time being. So in clinical practice, a non-operativetherapy for diabetic ulcer is badly needed, new medical techniques orpharmaceuticals are also in great demand.

DETAILED DESCRIPTION OF THE INVENTION

The technical problem to be resolved in this present invention is to usethe above-mentioned all known pharmaceutical composition for treatingthermal injuries to treat diabetic ulcer in limb or on body surface(diabetic ulcer for short).

Therefore, this present invention relates to use of pharmaceuticalcomposition in preparing pharmaceuticals for treating diabetic ulcer inlimb or on body surface, or in preparing medical dressing. The saidpharmaceutical composition consisting of (A) 3 to 15% of edible beeswax,and (B) 85 to 97% of sesame oil extract of Huangqin, Huanglian,Huangbai, earthworm and poppy capsule, based on the total weight of thepharmaceutical composition. In the sesame oil extract, each of Huangqin,Huanglian, Huangbai, earthworm and poppy capsule is in an amount of 2 to10% by weight of dry raw material based on the total weight of sesameoil.

The pharmaceutical compositions described in the present invention arefor external use. In the present techniques, pharmaceuticals forexternal use may include many dosage forms, e.g., solution, tincture,powder, lotion, oil, emulsion, ointment, paste, emplastrum, and gel,etc. Oil, emulsion, ointment, paste, emplastrum or gel is the preferredform for the pharmaceutical compositions in the present invention.

The pharmaceutical compositions described in the present inventionfurther comprise a carrier which is pharmaceutically acceptable.

The use of the present invention only relates to use of thepharmaceutical compositions described in the present invention inpreparing pharmaceuticals for treating diabetic ulcer in limb or on bodysurface, in other words, pharmaceutical compositions described in thepresent invention shall be used externally to treat diabetic ulcer. Thepresent invention does not relate to use of the pharmaceuticalcompositions described in the present invention in preparingpharmaceuticals used internally for treating diabetes, in other words,the present invention does not relate to the pharmaceutical compositionsdescribed in the present invention as pharmaceuticals used internallyfor treating diabetes itself.

This present invention still relates to a kind of medical dressing fortreating diabetic ulcer in limb or on body surface, the herein saiddressing includes pharmaceutical compositions consisting of thefollowing ingredients: (A) 3 to 15% of edible beeswax, and (B) 85 to 97%of sesame oil extract of Huangqin, Huanglian, Huangbai, earthworm andpoppy capsule, based on the total weight of the pharmaceuticalcomposition. In the sesame oil extract, each of Huangqin, Huanglian,Huangbai, earthworm and poppy capsule is in an amount of 2 to 10% byweight of dry raw material based on the total weight of sesame oil.

Medical cotton gauze and medical bandage are the preferred forms for theherein said medical dressing.

This present invention also relates to a kind of medicine box, whichincludes the pharmaceutical compositions described in the presentinvention or the herein said medical dressing, and Directions for Use.The medicine box integrates with the said pharmaceutical compositions orthe said medical dressing containing this said pharmaceuticalcompositions, meanwhile, at least one copy of Directions for Use isenclosed along with, making it more convenient to use the medicine boxof this present invention in clinical practice.

In this present invention, diabetic ulcers were treated with thepharmaceutical compositions described in the present invention andsatisfactory therapeutic effectiveness was obtained. For the treatmentof large area and serious diabetic ulcer, which is especially recognizedas a very knotty problem in modern clinical practice, the effectivenesswas remarkable. There was also very significant therapeuticeffectiveness in treating secondary ulcers of amputation wound surfaceafter first amputation of the lower extremities in diabetic patients.

The clinical implementation methods are as follows:

1. Bandaging Method

-   -   The pharmaceutical compositions of this present invention were        directly smeared 1 to 3 mm thick on the wound surface of        diabetic ulcer. The wound surface was covered and bound (not        very thick) with cotton gauze (or other similar ventilative        material) with the dressing change twice daily in morning and        evening or once daily (if in a less favourable condition). The        dressing change herein said means to remove the metabolites in        wound surface of diabetic ulcer and the residual pharmaceutical        composition with cotton swabs very gently first, then cover the        wound surface with new and the same pharmaceutical composition,        finally bind with gauze dressing. When necrotic musculotendinous        tissue appears on ulcerous wound surface, remove it with        scissors. During the whole treatment, disinfectants are        forbidden to use for disinfecting the ulcerous wound surface.

2. Exposed Method

-   -   The pharmaceutical composition of this present invention was        directly smeared on wound surface of diabetic ulcer, normally        thinner than 2 mm thick. The ulcerous wound surface was exposed        after covered with the pharmaceutical composition, then it        appears that the pharmaceutical composition covered on the        ulcerous wound surface begins to be warmed up and melted, some        white metabolites in wound surface also begin to be discharged        out of the drug layer, or mixed with the pharmaceutical        composition. On the whole, all the pharmaceutical composition on        wound surface will be turned into a white mixture of metabolites        within 6 to 8 hours, at this moment, remove this white mixture        with cotton swabs, and then cover the ulcerous wound surface        again with new and the same pharmaceutical composition. Change        new pharmaceutical composition whenever the applied        pharmaceutical composition is completely turned into white        mixture of metabolites. Repeat this process until healing of the        ulcerous wound surface. When necrotic musculotendinous tissue        appears on wound surface of the ulcer, remove it with scissors.        During the whole treatment, disinfectants are forbidden to use        for disinfecting the ulcerous wound surface.

3. Drug Gauze Method

-   -   Gauze was immersed in the pharmaceutical composition of this        present invention after the latter being warmed up and melted,        just like the process of making vaseline gauze. The ulcerous        wound surface was covered with the pharmaceutical composition        gauze, and then treated with bandaging method or semi-exposed        method. The gauze was changed once daily.

Diabetes is a disease that is characteristic of chronic hyperglycemia.Concomitant ulcers in the lower extremities, delayed healing of woundsurface, and other complications are also often seen. In the presenttechniques, most of the diabetic ulcers can often result in amputation,which is one of the major causes of disablement and death for diabeticpatients. There exists a direct or indirect relationship between thehyperglycemia, which is the most remarkable characteristic of diabetes,and difficult healing of ulcerous wound surface. Strict control of bloodsugar can effectively prevent the emergence and development of difficulthealing wound surfaces, but in many patients, even if the blood sugarlevel is controlled within the normal range, healing of diabetic ulceris still very difficult. In view of this circumstance, it is of greatsignificance to further carry on research on the mechanism of difficulthealing of diabetic ulcer, and find an effective and new method forimproving healing of diabetic ulcer. In the past, diabetic ulcers wereoften treated with surgical dressing change method, whose effectivenessis always not ideal.

This present invention reveals that, under effective control of bloodsugar, the pharmaceutical compositions of this present invention canremarkably promote healing of the diabetic ulcers.

Linoleic acid, as an active ingredient in the pharmaceutical compositionof this present invention, is a kind of essential fatty acid and anindispensable component of the plasma membrane. It is also an essentialsubstance for cellular repair after tissue injury, it can increasenutrition for local inflammatory wound surface and provide essentialnutritional medium for cellular repair of wound surface. Diabetes is akind of neurotrophic and metabolic disease. Diabetic ulcers always occurto toes, ankles and heels, indicating that the pathogenesis is closelyrelated to peripheral angiopathy and peripheral neurotrophy.

The key measure to topical treatment for diabetic ulcer is to removenecrotic tissue in time, because surface of chronic ulcer easily becomesdry and therefore is not easily to be cleared. Excision of necrotictissue by operation shall be sure to injure part of the normal tissue,especially when the tissue is in serious ischemia due to the use ofanesthetics containing epinephrine. Ointment form with frameconfiguration is preferred for pharmaceutical composition of thispresent invention. It is characteristic of oiliness and moisture, canremain in wound surface for longer time, keep wound surface moisturized,and make the necrotic tissue enzymolyzed and rancidified, and finallythe secretion in wound surface is excreted by ‘self drainage’, which isvery beneficial to the clearance of necrotic tissue. In the meantime, aphysiological environment for in situ stem cell differentiation is alsoestablished, leading to the activation of dormant stem cells andregeneration of tissue, therefore formation of scar and adhesion areprevented. Liquefaction and excretion of necrotic tissue last a littlelonger than that in general ulcers. A short term of bandaging method mayalso be adopted before the wound surface begins to repair. Relativelarger dosage can be used every time, with a thickness over 1.5 mm. Whennecrotic tissue begins to liquefy and excrete, shift to moisturizingexposed method, meanwhile, decrease the dosage for each time andincrease the times of administration. The characteristic of diabeticulcer change during the treatment with moisturizing exposed method isthat liquefaction and excretion of necrotic tissue is concomitant withthe formation of transparent membrane of lipoprotein. Once that thetransparent membrane forms, the ulcer repair is initiating. Specialattention should be paid to protect the integrity of this transparentmembrane of lipoprotein so as to assure that the whole process of repairfor the ulcer is always carried on beneath the transparent membrane oflipoprotein. After the basal tissue of skin forms, transparent membraneof lipoprotein shall disappear by itself. In this present invention,many cases in which diabetic ulcers are deep down to the fatty layerhave a longer course of disease, but still can be cured, One of themechanisms that the diabetic ulcer can be cured is regeneration of basalcells in ulcerous wound surface, and the other is the concentric growthof new skin around the ulcer.

The surface active substance in the pharmaceutical composition of thispresent invention is composed of hydrophilic groups and lipophilic-nonpolar groups; the pharmaceutical composition of this present inventionhas a higher surface activity and has solubilizing effect [Rongxiang Xu.Regenerative medicine: research, creation and prospect. Chinese Journalof Burns, Wounds and Ulcers, 2002, 14(2):122-130]. The two-stateconversion of the pharmaceutical composition of this present inventioneffectively segregates ulcerous wound surface, resulting in an effect ofanti-infection, i.e., to decrease bacterial infection, make bacterialose addiction to the live tissue, therefore, effectively decreasebacterial number and inhibit bacterial growth, with the final effect ofblocking, inhibiting and discharging the bacteria. Effective segregationof ulcer by the ointment also help maintain the enzymatic activity,diminish and block oxidation of unsaturated fatty acids and vitamin C,and effectively prevent formation of peroxides, protect cell membraneand fat from oxidation damage, and play a role in maintaining normalmetabolism of the tissue.

The pharmaceutical composition of this present invention effectivelysegregate ulcerous wound surface, and avoid stimuli of external factorsto exposed nerve endings, resulting in an analgesic effect. Besides thatthe pharmaceutical layer blocks the stimuli of foreign objects to woundsurface, other mechanisms that involve the said analgesic effect are:(1) beta-sitosterol and other ingredients in the pharmaceuticalcomposition of this present invention can effectively reduceinflammatory reactions; (2) the pharmaceutical itself is non-irritative;(3) the pharmaceutical improves local microcirculation, enhances localblood flow, promotes local metabolism, attenuates stimulatory effect oftissue ischemia, anoxia, edema on nerve endings. (4) in the course, aphysiological environment for in situ stem cell differentiation is alsoestablished, leading to the activation of the dormant stem cells andregeneration of the tissue, and these are all favorable to ulcerhealing.

The clinical application value of the pharmaceutical compositions ofthis present invention lies in as follows:

-   -   1 Improve the oxygen supply for diabetic ulcerous wound surface        especially for large area, serious diabetic ulcerous wound        surface and tissue, making the wound surface change from anoxia        and no vitality to oxygenation and vitality.    -   2. Relatively fast grows vital granulation tissue.    -   3. Gradually regenerates new healing wound surface of the skin        tissue from the granulation tissue.

In conclusion, the present invention has filled in the gaps of curingdiabetic ulcers with the pharmaceuticals in modern clinical medicine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Picture of diabetic ulcer in left external malleolus of thediabetic patient described in Example 7.

FIG. 2: Picture of pasting and smearing medical gauze on the ulcer ofthe diabetic patient described in Example 7.

FIG. 3: Picture of treatment progress of the ulcer in left externalmalleolus of the diabetic patient described in Example 7.

FIG. 4: Picture of treatment progress of the ulcer in left externalmalleolus of the diabetic patient described in Example 7.

FIG. 5: Picture of treatment progress of the ulcer in left externalmalleolus of the diabetic patient described in Example 7.

FIG. 6: Picture of the ulcer in left external malleolus of the diabeticpatient described in Example 8.

FIG. 7: Picture of pasting and smearing medical gauze on the ulcer forthe diabetic patient described in Example 8.

FIG. 8: Picture of pasting and smearing on the ulcer for the diabeticpatient described in Example 8.

FIG. 9: Picture of diabetic ulcer before treatment of the diabeticpatient described in Example 9.

FIG. 10: Picture of diabetic ulcer amid treatment of the diabeticpatient described in Example 9.

FIG. 11: Picture of diabetic ulcer after treatment of the diabeticpatient described in Example 9.

FIG. 12: Picture of diabetic ulcer before treatment of the diabeticpatient described in Example 10.

FIG. 13: Picture of diabetic ulcer after treatment of the diabeticpatient described in Example 10.

FIG. 14: Picture of diabetic ulcer after treatment of the diabeticpatient described in Example 10.

FIG. 15: Picture of diabetic ulcer after treatment of the diabeticpatient described in Example 10.

FIG. 16: Picture of treatment with emplastrum for the diabetic patientdescribed in Example 11 of Implementation.

FIG. 17: Picture of day 31 post treatment for the diabetic patientdescribed in Example 11.

FIG. 18: Picture of day 60 post treatment for the diabetic patientdescribed in Example 11.

FIG. 19: Picture of day 90 post treatment for the diabetic patientdescribed in Example 11.

FIG. 20: Picture of day 110 post treatment for the diabetic patientdescribed in Example 11.

EMBODIMENTS

Next, with the aid of attached pictures, the present invention will beexplained further by way of the following non-limited examples. Personsskilled in the art all know and agree that, without departing from thespirit of this present invention, many modifications can be made to thepresent invention, but, even so, all the said modifications will alsofall into the category of this present invention. In addition, all rawmaterial including Huangqin, Huanglian, Huangbai, earthworm and poppycapsule, sesame oil can be easily obtained in the market.

Example 1

In accordance with the method revealed in Example 1 in Chinese PatentZL931002761, and according to the detailed and the same raw materialrevealed, sesame oil extract of Huangqin, Huanglian, Huangbai, earthwormand poppy capsule is obtained. By mixing the above-mentioned sesame oilextract and beeswax, Pharmaceutical Composition 1 described in thepresent invention is obtained.

Example 2

According to the same method described in Chinese Patent ZL931002761,the pharmaceutical composition described in the present invention ismanufactured, except that 10 Kg of each of Huanglian, Huangqin andHuangbai pieces, 2 kg of each of earthworm and poppy capsule, 100 Kg ofsesame oil and 10 Kg of beeswax are used. By mixing the beeswax andsesame oil extract of Huangqin, Huanglian, Huangbai, earthworm and poppycapsule, Pharmaceutical Composition 2 is obtained.

Example 3

According to the same method described in Example 1 of the presentinvention, the pharmaceutical composition described in the presentinvention is manufactured, except that 8 Kg of each of Huanglian,Huangqin and Huangbai pieces, 3 kg of each of earthworm and poppycapsule, 100 Kg of sesame oil and 8 Kg of beeswax are used. By mixingthe beeswax and sesame oil extract of Huangqin, Huanglian, Huangbai,earthworm and poppy capsule, Pharmaceutical Composition 3 is obtained.

Example 4

According to the same method described in Chinese Patent ZL931002761,the pharmaceutical composition described in the present invention ismanufactured, except that 3 Kg of each of Huanglian, Huangqin andHuangbai pieces (prepared pieces in the art,), 4 kg of each of earthwormand poppy capsule, 100 Kg of sesame oil and 15 Kg of beeswax are used.By mixing the beeswax and sesame oil extract of Huangqin, Huanglian,Huangbai, earthworm and poppy capsule, Pharmaceutical Composition 4 isobtained.

Example 5

According to the same method described in Example 3 of the presentinvention, the pharmaceutical composition described in the presentinvention is manufactured, except that 10 Kg of each of Huanglian,Huangqin and Huangbai pieces, 10 kg of each of earthworm and poppycapsule, 100 Kg of sesame oil and 3 Kg of beeswax are used. By mixingthe beeswax and sesame oil extract of Huangqin, Huanglian, Huangbai,earthworm and poppy capsule, Pharmaceutical Composition 5 is obtained.

Example 6

The pharmaceutical compositions in the present invention obtained inExample 1 to 5 are warmed up and melted. According to the method knownto the persons skilled in the art, the medical gauze is immerseddirectly into each of the five pharmaceutical compositions respectivelyuntil it is completely soaked, thus medical dressing containing thepharmaceutical compositions of this present invention is obtained. Thedressing was packed into marketable medical products.

Example 7 Treatment for the Ulcer of the Malleolus Soft Tissue inDiabetic Patient

Diabetic patient, male, 59 years old, left external malleolus ulceratedfor 2 years, with an area of about 4×4 cm (see FIG. 1), diagnosed inconfirmation as diabetic ulcer. After admission, expectant treatment oflowering blood sugar was adopted, and the medical gauze described inExample 6 prepared from pharmaceutical composition manufacturedaccording to method described in Example 1 was used. The ulcerous woundsurface was pasted and covered with the dressing (see FIG. 2 and FIG.3), which was changed once daily. The patient was healed and dischargedafter treatment for one month (see FIG. 4 and FIG. 5).

Example 8 Treatment for the Ulcer of the Malleolus Soft Tissue inDiabetic Patient

Diabetic patient, male, 58 years old, left internal malleolus ulceratedfor 2 years, with an area of about 3.5×4 cm (see FIG. 6), diagnosed inconfirmation as diabetic ulcer. After admission, expectant treatment oflowering blood sugar was adopted, and the medical gauze described inExample 6 made from pharmaceutical composition manufactured according tomethod described in Example 2 used. The ulcerous wound surface waspasted and covered with the dressing (see FIG. 7), which was changedonce daily. The patient was healed and discharged after treatment forone month (see FIG. 8).

Example 9 Treatment for Diabetic Foot Ulcer

Diabetic patient, female, 42 years old, came to see the doctor afterleft foot ulcerated for 22 days and began to exacerbate. Amputation hadbeen advised by doctors but was rejected by her. On admission, fastingblood sugar in early morning was 22.67 mmol/L, and the patient wasclinically diagnosed in confirmation as diabetes. Serious diabetic ulcerappeared in the internal and lower site of the left foot, withremarkable swelling of left foot, intensive ulceration from externalportion of foot dorsum to middle and rear portion of planta, meanwhilefistulous tracts formed and linked up, phalanges of toes exposed,fasciae and muscles began to necrotize, ulcerate and was fetid (see FIG.9). After anti-infection and nutritional support therapy, the patientwas smeared with the pharmaceutical composition described in Example 3with a thickness of about 2 mm on the ulcer, subsequently the ulcerouswound surface which was covered with the pharmaceutical composition wascompletely exposed. The pharmaceutical was changed once daily (see FIG.10). After treatment for 45 days, the ulcer basically healed and thepatient was discharged from the hospital (see FIG. 11).

Example 10 Treatment for Diabetic Foot Ulcer

Male, suffered from diabetes for many years, blood sugar was notcontrolled very well in everyday life, a diabetic ulcer in leftmalleolus was clinically diagnosed, internal portion of distal end ofleft foot was obviously red and swelling, there were open wounds inhallux and phalangeal joint, joint capsule was damaged, bone articularsurface could be seen, there was necrotic tissue attached to internalportion of bone's distal end, muscle tendon swelled and denatured. Therewas a wound surface of 8×6 cm in planta, fetid and with secretion (seeFIG. 12). The patient was smeared with the pharmaceutical compositiondescribed in Example 4 with a thickness of about 1.5 mm on the ulcer,subsequently the ulcerous wound surface which was covered with thepharmaceutical composition was completely exposed. The pharmaceuticalwas changed once daily. After treatment for 35 days, the said ulcerhealed and the patient was discharged from the hospital (see FIG. 13,FIG. 14, FIG. 15).

Example 11 Treatment for Diabetic Foot Ulcer

Xu, male, 59 years old, suffered from diabetes for 20 years. He went tosee doctor in a Chinese provincial hospital because of his diabetic footgangrene. The doctor advised him to be amputated, but he did not agreeand then was transferred to The First Clinical Hospital affiliated toHarbin Medical University. Diagnosis on admission showed: (1) Type Idiabetes; (2) diabetic gangrene of right foot due to arterialobliteration in right leg for half a year. After management to ulcerouswound surface, the patient was treated with ointment form of thepharmaceutical composition described in Example 2, and emplastrum form(containing pharmaceutical composition described in Example 3) describedin Example 6 (see FIG. 16). The pharmaceutical was changed once dailyand the ulcer was treated with ointment and emplastrum alternativelyafter exposure. Ulcerous wound surface healed gradually [see FIG. 17(day 31), FIG. 18 (day 60)], on day 90, ulcerous wound surface basicallyhealed (see FIG. 19). After treatment for 110 days, ulcerous woundsurface healed well (see FIG. 20).

Example 12 Observation of Therapeutic Effectiveness on Diabetic Ulcersof the Lower Extremities in 60 Cases

In 60 cases of diabetic ulcer on leg, 36 cases were for male and 24 forfemale. Aged from 60 to 80 years old, all patients had symptoms ofpolyposia, diuresis, polyphagia, hypodynamia and so on. Tests repeatedlyshowed that level of fasting blood sugar was higher than 7.8 mmol/L,which was in accordance with the diagnosis of type II diabetes. Amongall the cases in which the ulcers of the lower extremities lasted from 1month to 26 months, 15 were acute ulcer, 45 were chronic ulcer. Amongall the latter that had accepted treatment in other hospitals, therewere 36 cases of toe ulcer, 9 cases for each of heel ulcer andmetatarsus ulcer, and 6 cases of pretibial ulcer. All the foot ulcerswere chronic and deep down to fatty layer and ulcerous wound surfaceslacked granulation tissue, dry and little exudative. The minimum areawas 2.0 cm×1.0 cm and the maximum area was 2.2 cm×5.5 cm. Foot ulcerswere surrounded by thick and hard callous tissue. 5 in 6 cases ofpretibial ulcer were caused by external wounds, all with area less than2.0 cm×3.5 cm, obvious red, swelling, itching and pain of thesurrounding skin. All the cases were divided into two groups byrandomization: 30 cases for observation group and 30 cases for controlgroup. There was no significant difference (P>0.05) in statisticsbetween the two groups in age, sex, disease phase, and the ulceroussize. As to treatment for primary diseases, besides intensifyingdietotherapy, reducing blood sugar level with corresponding drugs wasapplied for all cases. To avoid hypoglycemia and lactacidemia in elderlypatients, Acarbose was given. The blood sugar concentration wasregularly tested and the therapeutic plans were readjusted accordingly.The most ideal treatment effect for primary diseases is that the bloodsugar concentration is lower than 8.3 mmol/L.

In observation group (test group), the ulcerous wound surface and thesurrounding skin was disinfected with 1% povidone-iodine, cleaned withsterile normal salt solution, and the necrotic tissue was cleared withsterile forceps and scissors, then cleaned with sterile normal saltsolution or 3% hydrogen peroxide solution. All the ulcers in observationgroup were externally and topically applied povidone-iodine evenlyallowing the drug to infiltrate into the tissue for 1 to 2 minutes. Thenthe pharmaceutical composition of the present invention described inExample 1 was smeared on the ulcers with cotton swabs, wiped flat,maintained a thickness of 1.5 mm to 2.0 mm. Sterile gauze was placed onthe ointment, bandaged. With the sick legs raised, the pharmaceuticalwas changed once daily. The therapeutic strategy was changed tomoisturizing exposed method when the necrotic tissue began to liquefy.With a thickness of 1.0 mm, the pharmaceutical was changed twice daily.The liquefied necrotic tissue was cleared in time when changing thepharmaceutical each time.

In control group, the sterile gauze was soaked in 160,000 U ofGentamycin, and then applied to the ulcers bandaged with dressing oncedaily. When changing, liquefied mixture or the necrotic tissue in theulcers in two groups should be cleared away, until the granulationtissue grew and epithelization completely realized.

Using graph-drawing method and transparent graph paper to determine thehealing rate of ulcerous wound surface, to calculate the area ofulcerous wound surface, refer to Adobe Photoshop 7.0 and Osirissoftwares for details. The area before treatment was selected as theinitial area, and the area at the end of the research as time phasepoint area. Formula for calculating area: healed area=(initialarea)−(time phase point area); healing rate of ulcerous woundsurface=(healed area/lesion area)×100%. Healing+obviouseffectiveness+effectiveness=total effectiveness. Healing: completeepithelization, no exudate; Obvious effectiveness: healing rate is over80%, no secretion, granulation tissue grow obviously, fresh and liableto bleeding; Effectiveness: ulcerous wound surfaces shrink, but not upto 80%, exudate diminishes, granulation tissue proliferates, pale or notfresh; Ineffectiveness: ulcerous wound surfaces do not change or evenexpand, not fresh.

Through statistical processing, all data were expressed as (x±s).Statistical analysis including t test, x² test, and correlation analysisfor enumeration data were undertaken with SPSS11.0 statistics software.P<0.05 represents statistical significance.

In the above-mentioned cases, 6 cases of pretibial ulcers healed within4 weeks, and the healing course was similar to that of burns of deepsecond degree. The healed topical skin is flat. The shortest healingtime of chronic ulcers in toes and heels was 35 days and the longest was2 months. According to clinical observation, the whole healing course ofthis type of ulcer can be divided into three stages: Liquefaction andexcretion of necrotic tissue; formation of transparent lipoproteinmembrane; and regenerative healing. Time span for liquefaction andexcretion of necrotic tissue is related to the types of primary diseasesand necrotic intensification of ulcerous wound surface, but all necrotictissue can begin to liquefy after treatment for 3 to 4 days, andliquefaction and excretion will finish within 2 to 4 weeks. The secondand the first stages are linked up, i.e., transparent lipoproteinmembrane develops step by step during the liquefaction and excretion ofnecrotic tissue, and liquefaction and excretion of necrotic tissuefinishes when transparent lipoprotein membrane completely forms. Oncethat transparent lipoprotein membrane forms, regenerative repair willaccelerate, macroscopically, patch-like skin nails or skin islands growsand expands. Along with the treatment, callous tissue surrounding woundsurface will gradually exfoliate, newly grown skin will emerge and growconcentrically, and finally ulcerous wound surfaces repair themselves.

TABLE Comparison of therapeutic effectiveness between two groups.Obvious Total Mean Case effec- Effec- Ineffec- effec- healing Group No.Healing tiveness tiveness tiveness tiveness time (d) Control 30 9 12 6 327 47.30 ± group 20.40 Test 30 27 2 1 0 30 25.00 ± group 10.50 Note: x²test for the data of row × column table was adopted for comparison ofrate, x² values of effectiveness rate and healing rate are 22.71 and20.07 respectively, all are more than x

 = 12.84, therefore P < 0.05; x² test was also adopted for comparison ofmean healing times, t = 5.32, P < 0.01.

indicates data missing or illegible when filed

Example 13

A kind of medicine box was manufactured using pharmaceutical compositionobtained from Example 1, or medical dressing obtained from Example 6with a method known in the art. Finally, the printed Directions for Usewere combined with the respectively packed pharmaceutical compositions(e.g., ointment) or the said medical dressing (e.g., emplastrum) andbecame marketable medicine box after packing.

What is claimed is:
 1. A pharmaceutical composition for use in thetreatment of diabetic ulcer in limb or on body surface, consisting of(A) 3 to 15% by weight of edible beeswax and (B) 85 to 97% by weight ofsesame oil extract of Huangqin, Huanglian, Huangbai, earthworm and poppycapsule, based on the total weight of the pharmaceutical composition,while in the sesame oil extract, each of Huangqin, Huanglian, Huangbai,earthworm and poppy capsule is in an amount of 2 to 10% by weight, basedon the total weight of sesame oil.
 2. The pharmaceutical composition forthe use according to claim 1, wherein the diabetic ulcer is diabeticfoot ulcer.
 3. The pharmaceutical composition for the use according toany one of claims 1 to 2, wherein the pharmaceutical composition is forexternal application.
 4. The pharmaceutical composition for the useaccording to any one of claims 1 to 2, wherein the pharmaceuticalcomposition is applied in form of an oil, an emulsion, a paste, anemplastrum or a gel.
 5. The pharmaceutical composition for the useaccording to any one of claims 1 to 2, wherein the pharmaceuticalcomposition is comprised in a medical dressing.
 6. The pharmaceuticalcomposition for the use according to claim 5, wherein the medicaldressing comprises medical cotton gauze and medical bandage.
 7. Amedicine box, comprising a pharmaceutical composition as defined in anyone of claims 1 to 2 and instruction for use.
 8. The pharmaceuticalcomposition for the use according to claim 3, wherein the pharmaceuticalcomposition is applied in form of an oil, an emulsion, a paste, anemplastrum or a gel.
 9. The pharmaceutical composition for the useaccording claim 3, wherein the pharmaceutical composition is comprisedin a medical dressing.
 10. The pharmaceutical composition for the useaccording to claim 4, wherein the pharmaceutical composition iscomprised in a medical dressing.
 11. A medicine box, comprising apharmaceutical composition as defined in claim 3 and instruction foruse.
 12. A medicine box, comprising a pharmaceutical composition asdefined in claim 4 and instruction for use.
 13. A medicine box,comprising a pharmaceutical composition as defined in claim 5 andinstruction for use.
 14. A medicine box, comprising a pharmaceuticalcomposition as defined in claim 6 and instruction for use.